L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro.

1. The effect of L-NG-nitro arginine (L-NOARG) was compared with that of L-NG-monomethyl arginine (L-NMMA) on vasodilatation of the isolated aorta of the rabbit and perfused mesentery of the rat in response to acetylcholine (ACh) and sodium nitroprusside (NP). 2. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) produced concentration-related contraction of the rabbit aorta precontracted with phenylephrine (700-900 nM). Similarly, L-NOARG (10-200 microM) and L-NMMA (30-100 microM) elevated perfusion pressure of the noradrenaline (NA, 0.6-2.5 mM)-preconstricted rat mesentery preparation. 3. L-NOARG (1.5-100 microM) and L-NMMA (3-100 microM) caused concentration-related inhibition of the vasodilator effect of ACh (0.01-1.0 microM) on the rabbit aorta without influencing responses to NP (0.03-0.5 microM). L-NOARG methyl ester (30 microM) also inhibited ACh-induced vasorelaxation with similar potency to NOARG. L-arginine (30-150 microM) but not D-arginine (100 microM) caused graded reversal of the inhibitory effect of both L-NOARG (15 microM) and L-NMMA (30 microM). Complete reversal of the effect of both inhibitors was achieved with 150 microM L-arginine. L-Alanine (50 microM), L-arginosuccinic acid (5 microM), L-citrulline (50 microM), L-methionine (50 microM) and L-ornithine (50 microM) failed to reverse the inhibitory effect of L-NOARG (15 microM). 4. L-NOARG (10-200 microM) and L-NMMA (30-100 microM) inhibited the vasodilator effect of ACh (0.006-18.0 nmol) in the rat mesentery without affecting vasodilatation due to NP (1.1-11.1 nmol). L-Arginine (100 microM) but not D-arginine (100 microM) produced partial reversal of the effect of L-NOARG (30 microM) and L-NMMA (30 microM). 5. L- and D-N'-butyloxycarbonyl No-nitro arginine (100 microM) produced modest (approximately 20%) inhibition of the effect of ACh on the rabbit aorta; this effect was not reversible with L-arginine (100 microM). L-Namonocarbobenzoxy arginine (L-NMCA, 5O microM), L-N-NG-dicarbobenzoxy arginine (L-NDCA, 5 microM) and L-NG-tosyl arginine (50 microM) were inactive. 6. These results identify L-NOARG as a potent, L-arginine reversible inhibitor of endothelium-dependent vasodilatation. The available data suggests that L-NOARG, like L-NMMA, inhibits endothelial nitric oxide (NO) biosynthesis.